Atrial fibrillation (AF) is the most common rhythm disturbance in the US and other developed countries. AF significantly affects the lives of the afflicted, causing symptoms that range from palpitations to fatigue, weakness and activity intolerance, and substantially increasing the risks of stroke, congestive heart failure and death. The impact on public health is substantial, with more than 400,000 hospital admissions per year and $6-7 billion in healthcare costs. Adding to the problems caused by AF is the lack of safe and effective therapies for this rhythm disorder. Pharmacotherapy for AF has a long history of poor efficacy and potentially lethal side effects. Newer ablation strategies are making inroads in paroxysmal AF, but they are long, difficult procedures with less than optimal success rates and too frequent adverse events. We have proposed gene therapy as a new strategy to treat cardiac arrhythmias. In this proposal, we hypothesize that gene therapy-induced alterations in atrial conduction and refractory properties will prevent atrial fibrillation. To test this hypothesis, we will address 3 specific aims: (1) to define conditions for AF prevention with refractory period prolongation from KCNH2-G628S gene transfer;(2) to assess the relative contributions of IKur and IKr to atrial repolarization during AF and to AF prevention, and (3) to eliminate AF by prolonging atrial refractory properties in combination with increasing atrial connectivity and conduction. Successful completion of these aims will further our understanding of the mechanism responsible for sustaining AF and possibly allow translation of these findings into novel therapies. PUBLIC HEALTH RELEVANCE: Atrial fibrillation (AF) is the most common rhythm disturbance in the US and other developed countries. AF significantly affects the lives of the afflicted, causing symptoms that range from palpitations to fatigue, weakness and activity intolerance, and substantially increasing the risks of stroke, congestive heart failure and death. The impact on public health is substantial, with more than 400,000 hospital admissions per year and $6-7 billion in healthcare costs. Adding to the problems caused by AF is the lack of safe and effective therapies for this rhythm disorder. Pharmacotherapy for AF has a long history of poor efficacy and potentially lethal side effects. Newer ablation strategies are making inroads in paroxysmal AF, but they are long, difficult procedures with less than optimal success rates and too frequent adverse events. This proposal focuses on developing new therapies to treat and potentially cure AF. We have preliminary data showing that gene therapies can eliminate AF. In this proposal, we will further develop our understanding of these therapies and their potential use with AF.